Gonadal Dysfunction in Thalassemia 2

Gonadal Dysfunction in Thalassemia 2

With recent therapeutic advances survival of patients with β –thalassemia major, endocrine dysfunction becomes an important issue. Hypothalamic – pituitary and ovarian failure which present either with failure of puberty and primary amenorrhea or with secondary amenorrhea, is major problem in both adolescent and adult patients              (Al Rimawi et al., 2005). It is possible that early in the natural history of hypogonadotrophism, there is a transient reversible phase affecting GnRH-gonadotrophic hormones secretory dynamics. At this stage thalassemics may mimic other types of genetic iron storage disease (such as haemochromatosis), where the reversal of HH is possible (Chaterjee et al., 2000). 

Chaterjee et al. (2000) found low-normal GnRH stimulated gonadotrophin levels in 15 thalassemic girls who developed secondary amenorrhea. Studying the spontaneous pulsatile properties of LH, FSH in those thalassemic girls revealed progressive neurosecretory dysfunction of their gonadotrophins. Magnetic resonance imaging studies revealed structural abnormalities of the pituitary gland and its stalk in some of these patients.

Little is known about the ontogeny of hypothalamic-pituitary injury which ultimately causes such girls to cease having periods. Even during their menstrual cycles these patients had evidence of reduced spontaneous and induced gonadotrophin secretion. This is indicative of subtle damage to the hypothalamic GnRH pulse generator mechanism. Pituitary gonadotrophs suffered more severe damage than the hypothalamus. This early evidence of diminished H-P reserve suggested that they were likely to develop secondary amenorrhea at a late date. These thalassemic girls continued to have progressive deterioration in then H-P function within 2 years after the onset of amenorrhea. They had significantly lower GnRH stimulated gonadotrophin response, although no striking difference was observed in their basal gonadotrophin damage. Moreover the thalassemic girls had multiple pulse defects, marked diminution in amplitude and maximal levels, a significant increase in the percentage of sleep entrained pulses and the absence of pulse variability – characteristic of hypothalamic damage (Chatterjee et al., 1993).

Another striking point highlighted by Chatterjee et al. (1993), is that the derangement of H-P complex progresses in an irreversible fashion. Therefore, all patients who developed secondary amenorrhea became apulsatile for gonadotrophin secretion during the period of their study.

Investigations:

-         Routine biochemical analysis.

-         Bone age (x-ray on the wrist and hand)

-         Thyroid functions (TSH and FT4)

-         Hypothalamic-pituitary-gonadal functions:

§  GnRH stimulation test.

§  Sex steroids.

§  Pelvic ultrasound to assess ovarian and uterine size.

§  In selected cases, GH stimulation test.

§  In selected cases, insulin growth factor-1, insulin growth factor binding protein-3, plasma zinc (De Sanctis, 1995).

Treatment:

The treatment of delayed or arrested puberty and of hypogonadotrophic hypogonadism depends on factors such as age, severity of iron overload, damage to the HPG axis, chronic liver disease and the presence of psychological problems resulting from hypogonadism. Collaboration between endocrinologist and other doctors is critical.

For girls, therapy may begin with oral administration of ethinyl estradiol (2.5-5µg daily) for six months, followed by hormonal reassessment. If spontaneous puberty does not occur within six months after the end of treatment, oral oestrogen is re-introduced in generally increasing dosage (ethinyl estradiol from 5-10µg daily) for another 12 months. If breakthrough uterine bleeding does not occur, low oestrogen-progesterone hormone replacement is the recommended treatment (De Sanctis, 1995).

It is important that the treatment of pubertal disorders is treated on a patient-by-patient basis, taking account of complexity of the issues involved and the many associated complications (De Sanctis et al., 1995).